Slowly progressive frontotemporal lobar degeneration caused by the C9ORF72 repeat expansion: a 20-year follow-up study.

A hexanucleotide expansion in chromosome 9 open-reading frame 72 (C9ORF72) has been found to be a major cause of frontotemporal lobar degeneration (FTLD). We describe a 20-year follow-up of a unique case with very slowly progressive FTLD caused by the C9ORF72 repeat expansion. In serial neuropsychological examinations, the patient's cognitive decline was exceptionally slow and after 20 years the patient still was mainly independent in activities of daily living. Our case indicates that there is great individual variation in the progression and duration of C9ORF72-associated FTLD, and also language variants or mixed phenotypes may be present.

Parkinsonism associated with the homozygous W748S mutation in the POLG1 gene.

Parkinsonism has been described in patients with mutations in POLG1 gene. The W748S mutation is one of the most common mutations in this gene and it has been found to be a frequent cause of autosomal recessive ataxia in adults and the Alpers syndrome in children. We found the W748S mutation in a 65-year-old man with a late-onset syndrome consisting of ataxia, parkinsonism, ophthalmoplegia, peripheral neuropathy, and sensorineural hearing loss. Parkinsonism is one of the phenotypic features associated also with the W748S mutation.

Hereditary dementia with intracerebral hemorrhages and cerebral amyloid angiopathy.

BACKGROUND: Deposition of the beta-amyloid peptide (Abeta) in neuritic plaques is a hallmark of Alzheimer disease (AD). Mutations in genes encoding amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1, PSEN2) are associated with increased accumulation of Abeta in neuritic plaques or in the walls of cerebral vessels. Intracerebral hemorrhage occasionally affects patients with AD. METHODS: A Finnish family with dementia in four generations and with frequent co-occurrence of dementia and intracerebral hemorrhage was identified. Clinical features of 14 family members with a cognitive decline were evaluated. All exons in genes encoding APP, PSEN1, PSEN2, cystatin C, transthyretin, gelsolin, and ITM2B were sequenced, and an association study of APP was conducted by identification of single-nucleotide polymorphisms. RESULTS: Neuropathologic examination revealed Alzheimer-type changes with Abeta in neuritic plaques and vessel walls, but the cognitive profile of the patients differed from that in AD, as the visuoconstructive functions and verbal fluency were well preserved even in the moderate stage of the disease. In addition to cognitive decline, five patients had had lobar intracerebral hemorrhages and one was diagnosed with hemosiderin deposits in MRI, suggesting previous cerebral microbleeds. No causative mutations were identified in candidate genes associated with amyloid diseases, but linkage to APP region could not be entirely excluded. CONCLUSIONS: The family presents an autosomal dominant form of beta-amyloidogenic disease that resembles the Italian, Flemish, and Iowa types of AD. No amyloidogenic mutations were identified, but the role of the APP region could not be entirely excluded.

Contrast-enhanced dynamic and static MRI correlates with quantitative 99Tcm-labelled nanocolloid scintigraphy. Study of early rheumatoid arthritis patients.

OBJECTIVE: The aim of this study was to evaluate the roles of contrast-enhanced dynamic and static magnetic resonance imaging (MRI) and quantitative 99Tcm-labelled nanocolloid (NC) scintigraphy in detecting wrist joint inflammation in early rheumatoid arthritis (RA) patients. METHODS: Twenty-eight early RA patients (median symptom duration 5 months, range 1-12 months) underwent MRI, NC scintigraphy, laboratory and clinical examinations. Static wrist MRI scans were retrospectively scored for synovitis, bone oedema and erosions by two independent readers using the recently published rheumatoid arthritis MRI scoring system (RAMRIS). Twenty NC scans were analysed quantitatively by measuring maximum 99Tcm-NC uptake in three small areas of each wrist. From the same locations on the wrists, dynamic MRI gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA) enhancement rates (E-rate) were measured. The average 99Tcm-NC uptake of the whole wrist region was also measured and average E-rates were calculated. Correlations between MRI and NC scintigraphy measurements were calculated. Correlations between imaging methods of the wrist and the global measures of inflammation (laboratory and clinical examinations) were also assessed. RESULTS: Strong correlations emerged between maximal 99Tcm-NC uptake and MRI E-rates, reflecting similar performance of the methods in detecting local synovial inflammation. 99Tcm-NC uptake and MRI E-rate correlated with semiquantitative scoring of synovitis and bone oedema from static MRI scans. The erythrocyte sedimentation rate (ESR) correlated with MRI scores, E-rate and 99Tcm-NC uptake. No correlation between the clinical parameters and the imaging methods was detected. Inter-observer reliability for scoring synovial hypertrophy, bone oedema and bone erosions from static MR images were high (single-measure fixed-effects intra-class correlations 0.87, 0.93 and 0.91 respectively). Intra-observer reliability for E-rate and 99Tcm-NC measurements of 10 randomly picked scans was found to be high, with an intra-class correlation of 0.92; 95% confidence interval (CI) 0.84-0.96 and 0.99; 95% CI 0.98-1.00, respectively. CONCLUSIONS: Objective information about wrist joint inflammation can be obtained with contrast-enhanced dynamic MRI and quantitative 99Tcm-labelled NC scintigraphy. MRI also allows visualization and semiquantitative scoring of bone oedema and erosions of the wrist. Dynamic MRI and NC scintigraphy are safe and easy to perform, and they can be used in a long-term follow-up of rheumatoid patients.

Comparison of closed-loop and open-loop models in the assessment of cardiopulmonary and baroreflex gains.

OBJECTIVES: Both open- and closed-loop models of beat-to-beat cardiovascular control have been suggested. We tested whether the modelling yields different results with real data while assessing cardiopulmonary and baroreflex gains. METHODS: Two autoregressive models are described to resolve causal relationships between systolic blood pressure (SBP), RR-interval (RRI) and instantaneous lung volume (ILV): a closed-loop model which takes into account both the RRI changes induced by changes in SBP and the SBP changes mediated by changes in RRI, and an open-loop model which does not have a link from RRI to SBP. The performance of the models was compared in 14 healthy men in supine and standing positions under control conditions and under conditions of beta -sympathetic and parasympathetic pharmacological blockades. Transfer function gains were computed from ILV to RRI (cardiopulmonary gain) and from SBP to RRI (baroreflex gain). The measurements were done under controlled random-interval breathing. RESULTS: The gains identified by the open-loop model tended to be higher than those from the closed-loop model, but the differences did not reach statistical significance. Importantly, the two models discriminated the changes in transfer gains between different interventions equally well. CONCLUSIONS: Because the interactions between SBP and RRI occur physiologically in a closed-loop condition, the closed-loop model provides a theoretical advantage over the open-loop model. However, in practise, it seems to be little reason to select one over the other due to methodological errors when estimating cardiopulmonary or baroreflex transfer gains.

Ultrasonography of salivary glands in primary Sjogren's syndrome. A comparison with magnetic resonance imaging and magnetic resonance sialography of parotid glands.

OBJECTIVES: To evaluate ultrasonography (US) of salivary glands in primary Sjögren's syndrome (SS) and to compare US with parotid magnetic resonance (MR) imaging and MR sialography. METHODS: US examination of parotid, submandibular and sublingual glands was performed on 27 patients with primary SS, 27 healthy controls and 27 symptomatic controls without SS. The results were compared with parotid MR imaging and MR sialography and the clinical features of the patients. RESULTS: Salivary gland abnormalities, parenchymal inhomogeneity or adipose degeneration, were visualized in 21 (78%) SS patients, in one healthy control and in two symptomatic controls by US. Eighteen (67%) patients had changes in the parotid and submandibular glands and 8 (30%) changes in the sublingual glands. In the comparison, MR sialography was found to be the most sensitive method (96%), followed by MR imaging (81%) and US (78%), in detecting glandular changes. The specificity of US was 94%. The US and MR results were related to anti-Ro/SSA positivity but not to saliva secretion. The focus scores were related only to parotid MR imaging findings. CONCLUSIONS: US, MR imaging and MR sialography with modern technology have reached such a good accuracy in visualizing glandular structural changes that they are promising alternatives to the conventional invasive examinations in the diagnostics of SS.

Magnetic resonance imaging and magnetic resonance sialography of parotid glands in primary Sjogren's syndrome.

OBJECTIVE: To look for structural parotid gland changes on magnetic resonance (MR) imaging and MR sialography of primary Sjögren's syndrome (SS) patients and healthy control subjects and to compare these methods with each other. METHODS: MR imaging and MR sialography of both parotid glands were performed on 26 patients and 7 healthy controls. Bilateral surface coils were used to obtain high spatial resolution. RESULTS: Twenty-two of the 26 patients had abnormalities on MR imaging. Twenty-one had a nodular or dendritic parenchymal pattern, 5 had cavities, and 6 had duct dilatations. On MR sialography, 25 of the 26 patients had abnormalities of the ducts, and 16 of them also had cavities. One patient and all 7 controls had normal results with both methods. The structural appearance of the parotid glands on MR images had marginal linear association with the duct system changes but no correlation with the cavitary changes seen on MR sialography. Furthermore, duct system abnormalities did not correlate with cavitary changes. Both parenchymal and sialographic abnormalities were associated with the presence of Ro/SSA antibodies but not with age of the patient, disease duration, salivary flow rate, or the presence of hypergammaglobulinemia or extraglandular manifestations. CONCLUSION: MR imaging and MR sialography are noninvasive methods that provide definitive information of morphologic changes in parotid glands and can be used as diagnostic indicators of primary SS. Because these methods give information on different aspects of glandular pathology, both should be performed when evaluating parotid glands of SS patients. MR sialography is more sensitive, but conventional MR imaging gives complementary information on the progressive pathologic changes of glandular parenchyma.

Circadian systemic haemodynamics in borderline and mild hypertension.

Circadian variations in blood pressure (BP), stroke volume (SV), heart rate (HR), cardiac output (CO) and total peripheral resistance (TPR) were determined by a pulse contour method from the intra-arterial pulse wave in 32 normotensive (NT), 32 borderline hypertensive (BHT) and 31 hypertensive (HT) middle-aged men. Daytime averages were used as the reference levels. The nocturnal decrease in BP and HR were similar in the three groups. In the night, SV did not change in the NT group, but was increased in the BHT and HT groups. The nocturnal increase in SV may reflect reduced venous capacity causing increased cardiac filling. As a consequence of the difference in SV, the nocturnal CO fall was diminished in the HT group as compared with the NT group. Moreover, TPR had a tendency to decrease in the HT group, which may be considered as a baroreflex response to buffer the expected rise in BP. Five years later, 25 NT, 24 BHT and 19 HT subjects were reassessed using casual BP measurements. In the NT and BHT groups, six and 17 subjects, respectively, had progressed to hypertension. In a logistic regression model for those who became HT, the nocturnal increase in SV was a significant predictor for future hypertension. In conclusion, the results suggest that circadian systemic haemodynamics may be altered before BP is markedly elevated, and that haemodynamic studies might be useful in predicting the development of sustained hypertension.

Wide-band spectral analysis of blood pressure and RR interval variability in borderline and mild hypertension.

The aim of this study was firstly to investigate whether indices of wide-band spectral analysis in borderline hypertensive (BHT) or mildly hypertensive (HT) subjects differ from those in normotensive (NT) subjects, and secondly to assess the predictive value of these indices for future hypertension. Electrocardiogram and intra-arterial 24 h ambulatory blood pressure (BP) were recorded in 32 NT, 29 BHT and 30 HT middle-aged men. From the recordings, a 16 h period was extracted for wide-band spectral analysis. A single spectrum of BP and RR interval (RRI) variability was computed for each period by the fast Fourier transform method. The slopes of the spectra were assessed on a log-log scale by linear fitting of the spectral values. Power spectral densities were calculated over regions of 0-0.003, 0.003-0.04, 0.04-0.15, 0.15-0.40 and 0-0.4 Hz. No between-group differences were found in the slopes of BP and RRI spectra. The between-group differences in spectral powers for BP variability were almost invariably significant. The spectral powers for RRI variability did not show between-group differences. Five years later, 22 NT, 22 BHT and 18 HT subjects were re-assessed using casual BP measurements. In a logistic regression model for the combined group of NT and BHT subjects who became HT (22 of 44) during the five-year period, none of the parameters of wide-band spectrum predicted the development of hypertension. In conclusion, parameters of wide-band spectral analysis may not be useful in predicting future hypertension in NT and BHT subjects. Because the BP level is a major factor influencing BP variability, the between-group differences in wide-band spectral powers in BP may be due to differences in BP level rather than differences in cardiovascular regulatory mechanisms.

Circadian profile of low-frequency oscillations in blood pressure and heart rate in hypertension.

Electrocardiogram and intraarterial blood pressure (BP) were recorded in 35 normotensive (NT), 29 borderline hypertensive (BHT), and 30 mildly hypertensive (HT) men (aged 35 to 45 years) by the Oxford method over a 24-h period. Consecutive data segments of 5 min were extracted from the recordings for frequency domain analysis. Heart rate (HR) and BP variability was calculated for oscillations between 0.05 and 0.12 Hz, usually referred to as Mayer waves. Power and median frequency of the oscillations were determined. Some 10% of the segments were excluded from the analysis because of artifacts and transients. The results were averaged for 5-h periods in the evening, at night, and during the day. In the BHT subjects, the median frequency of the Mayer waves was shifted to lower frequencies as compared with the NT subjects. This was seen at night and during the day. The phenomenon presumably reflects an increased latency in the sympathetic vasomotor control of the baroreceptor reflex. No between-group differences were found in the normalized spectral power values. Five years later, 24 NT, 22 BHT, and 19 HT subjects were reassessed using casual BP and noninvasive ambulatory 24-h monitoring. In the initial phase, the median frequencies for the 5-h periods showed no evident linear relationship with the corresponding BP levels. However, the median frequencies showed high inverse correlations with the follow-up ambulatory BP levels. In the evening and during the day, the median frequency showed a significant inverse correlation also with the increment in BP. No clear relationship was found between power estimates and BP levels or future increments in BP. In conclusion, the frequency shift of Mayer waves to lower frequencies is associated with an increased risk of developing established hypertension.

Simultaneous videofluorographic and dual-channel electroglottographic registration of the vertical laryngeal position in various phonatory tasks.

Simultaneous tracking of the vertical laryngeal position in various phonatory tasks was performed for 2 subjects (one male, one female) using dual-channel electroglottography (EGG) and videofluorography (videofluoroscopy). The tasks included phonation on [a:] with voluntary repeated (1) heightening and (2) lowering of the laryngeal position; alternation between [a:] and phonation on (3) [b], (4) [m], and (5) the voiced bilabial fricative [beta:]; and (6) production of the corner vowels [a, i, u]. EGG and videofluorography agreed about the direction of changes in the vertical laryngeal position in most cases. Most disagreements were found in the amount of changes. Reasons for the discrepancies, including, for example, changes in the resting position of the larynx and anteroposterior movements of the cartilages, are discussed. It can be concluded that dual-channel EGG is a valuable clinical and pedagogical tool for the analysis of the vertical displacement of larynx in well-specified phonatory tasks. The method should act most reliably on separately phonated vowels. Its applicability for studying laryngeal biomechanics more wholistically, however, is limited.

Evaluation of humeral head erosions in rheumatoid arthritis: a comparison of ultrasonography, magnetic resonance imaging, computed tomography and plain radiography.

The value of ultrasonography (US), magnetic resonance imaging (MRI), computed tomography (CT) and plain radiography (PR) in detecting bone erosions on the humeral head was evaluated in a study of 26 in-patients (26 shoulders) with rheumatoid arthritis (RA). MRI depicted humeral erosions in 25 (96%), US in 24 (92%), CT in 20 (77%) and PR in 19 (73%) of the 26 shoulders. MRI and US were superior to CT in detecting small erosions. US was the most sensitive method to show surface erosions on the greater tuberosity. US, CT and MRI detected large erosions quite similarly. PR frequently missed small erosions. In the evaluation of early erosions in the rheumatoid shoulder, US and MRI are more sensitive methods than the traditionally used PR. US and MRI are suitable for the evaluation of soft-tissue involvement in the rheumatoid shoulder, but also for the detection of bone erosions of the humeral head.

Sonography and MRI in the evaluation of painful arthritic shoulder.

We evaluated 31 painful shoulders of 30 patients with chronic arthritis by ultrasonography (US) and compared the results with those of magnetic resonance imaging (MRI). Both US and MRI revealed effusion in the subacromial-subdeltoid (SA-SD) bursa, biceps tendon sheath (BTS) and glenohumeral (GH) joint, but MRI was more accurate in depicting joint inflammation because of its ability to visualize synovial hypertrophy. US visualized biceps tendon ruptures equally well as MRI. MRI was better able to reveal full-thickness tear of the supraspinatus tendon, whereas US showed better other changes of the supraspinatus tendon (degeneration or partial-thickness tear). Both of the imaging methods were able to depict erosions of the humeral head, but the locations occasionally differed. Inexpensive and easily available US can be recommended as the first imaging method for the detection of soft-tissue changes in the arthritic shoulder, but in rotator cuff problems both methods may be needed.

Ultrasound evaluation of the acromioclavicular joint.

OBJECTIVE: To evaluate the value of ultrasonography in assessing arthritic acromioclavicular (AC) joints. METHODS: One hundred twenty-six AC joints of 63 healthy subjects (2 groups) were prospectively examined by ultrasound to determine the-normal limits of capsular distention and the width of the joint space. Thirty-three AC joints of 32 patients with chronic arthritis were evaluated by ultrasound and, for comparison, by radiography, computed tomography (CT), and magnetic resonance imaging (MRI). RESULTS: The mean ultrasonographic distance of the joint capsule from the bone rim was 2.2 mm +/- standard deviation (SD) 0.5 mm in 21-32-year-old control subjects and 2.9 +/- 0.7 mm in 37-81-year-old control subjects. The mean width of the joint space was 4.1 +/- 0.9 mm and 3.5 +/- 0.9 mm in the same control groups, respectively. In detecting soft tissue changes in arthritic AC joints MRI was better than ultrasound. In revealing bony surface changes, CT was the best method and radiography was least sensitive but quite specific. Our most prominent finding was that ultrasound is able to exclude joint inflammation; when the ultrasonographic distance of the joint capsule from the bone rim was < 3 mm, there was no synovial hypertrophy or effusion on MRI scans. CONCLUSION: Ultrasound can detect AC joint changes reliably. It is able to exclude joint inflammation. Effusion in the AC joint may reflect inflammation, but may also be a sign of degeneration.

Frequency shift in baroregulatory oscillation in borderline hypertensive subjects.

The aim of this study was to quantify the frequency shift in vasomotor oscillations in blood pressure we observed in borderline hypertensive individuals in our previous study. Electrocardiogram and intraarterial blood pressure were recorded in 33 normotensive, 29 borderline hypertensive, and 33 mildly hypertensive men (aged 35 to 45 years). Five-minute stationary periods in supine, sitting, and standing positions, and during sleep were extracted from the recordings for autoregressive frequency domain analysis. In borderline hypertensive subjects vasomotor oscillations in the range of 0.05 to 0.12 Hz in blood pressure and heart rate, assumed to be associated with baroreceptor activity, were shifted to lower values as compared with the other two groups. The frequency shift was assessed by median frequency of the oscillations. Significant between-group differences were observed in the supine and sitting positions. No significant between-group differences were seen in normalized spectral power estimates. Further studies are required to determine whether the frequency shift provides prognostic information on cardiovascular morbidity.

Multivariate autoregressive model with immediate transfer paths for assessment of interactions between cardiopulmonary variability signals.

Multivariate autoregressive modelling provides a method to analyse the dynamic interactions between heart rate (HR), blood pressure (BP) and respiration (RESP) by means of noise source contributions (NSCs). The conventional approach presumes the modelled noise sources are mutually independent. This presumption is, in general, not satisfied and causes an error in the results. In the present study, the effect of this error is analysed. A method is presented to remove the error by making the noise sources independent. The method is based on the inclusion of immediate transfer paths in the model. To quantify the strength of the interactions, a measure called NSC ratio (NSCR); is calculated; this states the amount of variability of the signal arising from other signals. The method is demonstrated by studying the inter-relationships between HR, BP and RESP in a healthy male subject in supine and standing positions. It is found that the error is marked and that the presented method provides corrected estimates for spectral decomposition and NSC analysis. The results show it is necessary to include the immediate transfer mechanisms in the model, while analysing the cardiopulmonary dynamics by means of HR and BP variability.

Short-term variability of blood pressure and heart rate in borderline and mildly hypertensive subjects.

Electrocardiogram and intra-arterial blood pressure were recorded in 96 men (aged 35 to 45 years) by the Oxford method over a 30-hour period. The study involved 33 normotensive, 29 borderline hypertensive, and 34 mildly hypertensive individuals, as assessed by the cuff method. Five-minute periods during sleep and with subjects in supine, sitting, and standing positions were extracted from the recordings for frequency domain analysis. Power spectrum density estimates of systolic blood pressure, diastolic blood pressure, and heart rate were calculated by an autoregressive method over the bandwidths of 0.02 to 0.075 (low-frequency), 0.075 to 0.15 (midfrequency), and 0.15 to 0.35 Hz (high-frequency), attributable to thermoregulatory, baroreceptor, and respiratory activity. No significant intergroup differences were observed at nighttime, but in different body positions the borderline hypertensive subjects frequently had either greater low-frequency variability or smaller midfrequency variability than the other groups. In this respect, the power spectra for systolic and diastolic blood pressures provided better statistical differentiation between the groups than those for heart rate. Furthermore, the borderline hypertensive subjects exhibited attenuated night-day changes in the low-frequency band for all time series. The results suggest that in borderline hypertension the baroreceptor oscillations are shifted to lower frequencies, presumably reflecting altered function of the sympathetic nervous system. In conclusion, spectral analysis of blood pressure variability for controlled test situations made it possible to detect differences in the cardiovascular regulatory systems between normotensive, borderline hypertensive, and mildly hypertensive individuals.

Second derivative of developed tension in classifying cardiotonics with respect to their mechanisms of action: drugs affecting cAMP metabolism.

The second derivative of developed tension (T", d2T/dt2) has not come into common use in the analysis of cardiac contractility, although it has been shown to give additional information on the myocardial contraction-relaxation cycle (CRC). In the present study a new way to use T" in the analysis of myocardial mechanics, including the time course of T", is described. Profiles of the T" of the some drugs with established cardiotonic effects are presented. Experiments were carried out in spontaneously beating whole rat atria preparations. The effects of changing contraction frequency on the measured parameters were studied with electrically paced left atria. Qualitative inotropic effects of 1-methyl-3-isobutylxanthine (MIX), theophylline, caffeine, milrinone, isoprenaline and forskolin were studied. Concentrations equieffective with respect to the force of contraction were tested. Inotropic profiles were evaluated at the time of maximal force of contraction. We found that methylxanthines have a mechanical behaviour quite distinct from other inotropic agents acting via cAMP. The effects of MIX were similar to those of theophylline in all respects. A tendency to increase the active relaxation phase of T" was a property common to methylxanthines. Caffeine also prolonged the phases of contraction, whereas MIX and theophylline have opposite effects. Milrinone in turn mimics the effects of isoprenaline and forskolin; abbreviation of the relaxation phase of T" was the feature most typical of them. Caffeine was the only agent which did not shorten the duration of CRC. The method proved valuable in basic research on drug effects on cardiac contractility.