Effect of the duration of previous osteoporosis treatment on the effect of romosozumab treatment.

The effect of romosozumab is affected by previous osteoporosis treatment. Here we showed that the duration of the previous treatment just before romosozumab affects the therapeutic effect of romosozumab. Using denosumab and oral bisphosphonates for more than 1 year attenuates the effect of romosozumab. INTRODUCTION: As an anti-sclerostin antibody, romosozumab suppresses bone resorption and stimulates bone formation. We investigated whether the effectiveness of 12 months of romosozumab treatment depended on the duration of previous treatment with teriparatide, denosumab, or oral bisphosphonates. METHODS: In total, 259 osteoporosis patients received subcutaneous injections of romosozumab (210 mg) every 4 weeks during 2019 and 2020. This study was designed as a pre-post comparison. The end points were the percent changes of bone mineral density (BMD) after 12 months of romosozumab treatment. The patients were divided into seven groups depending on the type and duration of previous treatment before starting romosozumab as follows: non-previous treatment group, change from teriparatide used for 1 year or less/more than 1 year, change from denosumab used for 1 year or less/more than 1 year, and change from oral bisphosphonates used for 1 year or less/more than 1 year. RESULTS: The effects of previous treatment with teriparatide on the effectiveness of 12-month romosozumab did not clearly depend on the duration of treatment (p > 0.05). In contrast, the effects of previous treatments with denosumab or oral bisphosphonates on the effectiveness of 12-month romosozumab depended on the previous treatment duration, which was reflected by the differences in percent change of the spine BMD (both p < 0.05), however, there were no significant differences in the percent change of the total hip BMD (both p > 0.05). CONCLUSION: The duration of the previous treatment affected the effectiveness of romosozumab. Using denosumab and oral bisphosphonate for more than 1 year attenuated the effect of romosozumab.

Early clinical effects, safety, and predictors of the effects of romosozumab treatment in osteoporosis patients: one-year study.

Romosozumab is an effective treatment for spine osteoporosis because it reduces the incidence of new fractures and significantly increases the percent change in the spine BMD at 12 months. The percent change in the spine BMD is higher in patients not previously treated with other anti-osteoporosis medications. INTRODUCTION: Romosozumab appeared as a new osteoporosis medication in Japan in 2019. It is an anti-sclerostin antibody, which increases bone formation and suppresses bone resorption. The aim of our study was to elucidate the clinical effects, safety, and predictors of the effects of one-year romosozumab treatment. METHODS: This study was an observational study designed as a pre-post study in 262 patients. Romosozumab (210 mg) was administered subcutaneously once every 4 weeks during 12 months. We focused on incidence of new fractures, safety, bone mineral density (BMD) at the spine and total hip, and bone metabolism markers. RESULTS: There were five cases of new fractures during one-year romosozumab treatment. There were no fatal adverse events. Percent changes from baseline in the spine and total hip BMD after 12 months of romosozumab treatment were 10.67% and 2.04%, respectively. Romosozumab had better effects in cases of severe osteoporosis with low spine BMD, high TRACP-5b, and high iP1NP at the start of romosozumab treatment. The percent change in the spine BMD at 12 months was significantly lower in the group transitioning from bisphosphonates than in the group not previously treated with other anti-osteoporosis medications. CONCLUSION: Romosozumab is an effective treatment for spine osteoporosis because it significantly increases the percent change in the spine BMD at 12 months. The percent change in the spine BMD is higher in patients not previously treated with other anti-osteoporosis medications.

Early clinical effects, safety, and appropriate selection of bone markers in romosozumab treatment for osteoporosis patients: a 6-month study.

Our 6-month study showed the usefulness of romosozumab for preventing fractures and its safety. It was effective in patients with low baseline spine BMD, high TRACP-5b, and high iP1NP. Percent change from baseline of TRACP-5b and iP1NP after 1 month correlated with that from baseline of BMD after four to 6-month treatment. INTRODUCTION: Romosozumab appeared as a new osteoporosis medication in Japan in 2019. It is an anti-sclerostin antibody which increases bone formation and suppresses bone resorption. In this study, we analyzed the actual clinical effects, adverse effects, and the optimal way to evaluate the treatment. METHODS: Romosozumab was administered as subcutaneous injection of 210 mg once every 4 weeks. We conducted pre-post study in 185 patients treated for 6 months. We focused on the incidence of new vertebral fractures, safety, bone mineral density (BMD) at the spine and total hip, and bone metabolism markers. We evaluated BMD before romosozumab treatment and after 4 to 6 months and performed the serum analysis before romosozumab treatment, after 1, 3, and 6 months. RESULTS: There was no new fracture during treatment, and there was no fatal adverse event including cardiovascular disease. Since percent changes from baseline of the spine and total hip BMD were 6.34% and 1.53% after 4- to 6-month treatment, the treatment was effective for spine osteoporosis. Tartrate-resistant acid phosphatase 5b (TRACP-5b) and intact type I procollagen N-terminal propeptide (iP1NP) had significant changes during romosozumab treatment (p < 0.05). Percent change from baseline of TRACP-5b and iP1NP after 1 month correlated with percent change from baseline of BMD after 4 to 6 months of treatment. CONCLUSION: Romosozumab is effective in preventing fractures and useful for increasing the spine BMD. Also, romosozumab is relatively safe to use. It is especially effective in patients with low baseline spine BMD, high TRACP-5b, and high iP1NP.

Optimal MR Plaque Imaging for Cervical Carotid Artery Stenosis in Predicting the Development of Microembolic Signals during Exposure of Carotid Arteries in Endarterectomy: Comparison of 4 T1-Weighted Imaging Techniques.

BACKGROUND AND PURPOSE: Preoperative identification of plaque vulnerability may allow improved risk stratification for patients considered for carotid endarterectomy. The present study aimed to determine which plaque imaging technique, cardiac-gated black-blood fast spin-echo, magnetization-prepared rapid acquisition of gradient echo, source image of 3D time-of-flight MR angiography, or noncardiac-gated spin-echo, most accurately predicts development of microembolic signals during exposure of carotid arteries in carotid endarterectomy. MATERIALS AND METHODS: Eighty patients with ICA stenosis (≥70%) underwent the 4 sequences of preoperative MR plaque imaging of the affected carotid bifurcation and then carotid endarterectomy under transcranial Doppler monitoring of microembolic signals in the ipsilateral middle cerebral artery. The contrast ratio of the carotid plaque was calculated by dividing plaque signal intensity by sternocleidomastoid muscle signal intensity. RESULTS: Microembolic signals during exposure of carotid arteries were detected in 23 patients (29%), 3 of whom developed new neurologic deficits postoperatively. Those deficits remained at 24 hours after surgery in only 1 patient. The area under the receiver operating characteristic curve to discriminate between the presence and absence of microembolic signals during exposure of the carotid arteries was significantly greater with nongated spin-echo than with black-blood fast spin-echo (difference between areas, 0.258; P < .0001), MPRAGE (difference between areas, 0.106; P = .0023), or source image of 3D time-of-flight MR angiography (difference between areas, 0.128; P = .0010). Negative binomial regression showed that in the 23 patients with microembolic signals, the contrast ratio was associated with the number of microembolic signals only in nongated spin-echo (risk ratio, 1.36; 95% confidence interval, 1.01-1.97; P < .001). CONCLUSIONS: Nongated spin-echo may predict the development of microembolic signals during exposure of the carotid arteries in carotid endarterectomy more accurately than other MR plaque imaging techniques.

Carotid plaque characterization using 3D T1-weighted MR imaging with histopathologic validation: a comparison with 2D technique.

BACKGROUND AND PURPOSE: 3D FSE T1WI has recently been used for carotid plaque imaging, given the potential advantages in contrast and spatial resolutions. However, its diagnostic performance remains unclear. Hence, we compared the ability of this technique to readily assess plaque characteristics with that of conventional images and validated the results with histologic classification. MATERIALS AND METHODS: We prospectively examined 34 patients with carotid stenosis who underwent carotid endarterectomy by using 1.5T scanners and obtained 3D-FSE T1WI and 2D spin-echo T1WI scans. After generating reformatted images obtained from the 3D-FSE T1-weighted images, we calculated the contrast ratios for the plaques and the adjacent muscles and compared these findings with the pathologic classifications. RESULTS: Carotid plaques were histologically classified as types VII, VIII, IV-V, or VI. With 3D-FSE T1WI, the range of contrast ratios for each classification was the following: 0.94-0.97 (median, 0.95), 0.95-1.29 (median, 1.10), 1.33-1.54 (median, 1.42), and 1.53-2.12 (median, 1.80), respectively. With 2D imaging, the range of contrast ratios for each classification was the following: 0.79-1.02 (median, 0.90), 0.88-1.19 (median, 1.01), 1.17-1.46 (median, 1.23), and 1.55-2.51 (median, 2.07), respectively. Results were significantly different among the 4 groups (P < .001). Sensitivity and specificity for discriminating vulnerable plaques (IV-VI) from stable plaques (VII, VIII) were both 100% for the 3D technique and 100% and 91%, respectively, for the 2D technique. CONCLUSIONS: 3D-FSE T1WI accurately characterizes intraplaque components of the carotid artery, with excellent sensitivity and specificity compared with those of 2D-T1WI.

Predicting carotid plaque characteristics using quantitative color-coded T1-weighted MR plaque imaging: correlation with carotid endarterectomy specimens.

BACKGROUND AND PURPOSE: MR plaque imaging is used to evaluate the risk of embolic complications during carotid endarterectomy and carotid artery stent placement. However, its performance for characterizing intraplaque components has varied across studies and is generally suboptimal. Hence, we correlated MR imaging results with histologic findings to determine whether a combination of high-contrast T1-weighted imaging and quantitative image analysis could readily determine plaque characteristics. MATERIALS AND METHODS: We prospectively examined 40 consecutive patients before carotid endarterectomy by using a 1.5T scanner and axial T1-weighted spin-echo images under optimized scanning conditions. The percentage areas of intraplaque fibrous tissue, lipid/necrosis, and hemorrhage were calculated automatically by using the software with previously reported cutoff values and were compared with those of the specimens. The thickness of the fibrous cap was also measured manually. RESULTS: The percentage areas of fibrous, lipid/necrotic, and hemorrhagic components were 5.7%-98.7%, 1.3%-65.7%, and 0%-82.0%, respectively, as determined by the MR images, whereas the corresponding values were 4.8%-92.3%, 7.0%-93.8%, and 0%-70.4%, respectively, as determined by histologic examination. Significant positive correlation and agreement were observed between MR images and histologic specimens (r = 0.92, 0.79, and 0.92; intraclass correlation coefficients = 0.91, 0.67, and 0.89; respectively). Thickness of the fibrous caps on MR images (0.21-0.87 mm) and in the specimens (0.14-0.83 mm) also showed positive correlation and agreement (r = 0.61, intraclass correlation coefficient = 0.59). CONCLUSIONS: Quantitative analysis of high-contrast T1-weighted images can accurately evaluate the composition of carotid plaques in carotid endarterectomy candidates.

Prediction of carotid plaque characteristics using non-gated MR imaging: correlation with endarterectomy specimens.

BACKGROUND AND PURPOSE: Electrocardiographic gating, commonly used in MR carotid plaque imaging, can negatively affect intraplaque contrast if the TR is inappropriate. The present study aimed to determine whether a non-gated technique with appropriate TRs can accurately evaluate intraplaque characteristics in specimens excised by CEA. MATERIALS AND METHODS: We prospectively examined 40 consecutive patients who underwent CEA (59-82 years of age) by using a 1.5T scanner. Axial T1WI with a TR of 500 ms and PDWI and T2WI with a TR of 3000 ms with a self-navigated rotating-blade scan instead of cardiac gating were obtained. Signal intensities of the plaque and adjacent muscle were measured, and the CR on T1WI, PDWI, and T2WI as well as the gray-scale median on US were correlated with the pathologic findings of the CEA specimens. RESULTS: On T1WI, the CRs of the carotid plaques differed significantly among groups in which the main components were histologically confirmed as fibrous tissue, lipid/necrosis, and hemorrhage (0.54-1.17, 1.16-1.53, and 1.40-2.29, respectively). The sensitivity and specificity for discriminating lipid/necrosis/hemorrhage from fibrous tissue were 96% and 100%, respectively. On T2WI, the CRs of plaques with lipid/necrosis were significantly higher than those of other groups, but the CRs on PDWI and the gray-scale median on US were not significantly different among the groups. CONCLUSIONS: Non-gated MR plaque imaging, particularly T1WI, can readily predict the intraplaque main components of the carotid artery with high sensitivity and specificity.

Cabergoline scavenges peroxynitrite enhanced by L-DOPA therapy in patients with Parkinson's disease.

Long-term or high-dose L-DOPA therapy in patients with Parkinson's disease (PD) may accelerate degeneration of dopaminergic neurons, possibly by increasing oxidative stress. To investigate the effects of cabergoline on peroxynitrite-mediated oxidative damage caused by L-DOPA, the concentration of 3-nitrotyrosine in cerebrospinal fluid (CSF) of 18 PD patients was compared with that in 20 normal controls. The concentration of 3-nitrotyrosine in patients following L-DOPA therapy was significantly higher than in untreated PD patients and controls. On the other hand, the concentration in PD patients after cabergoline therapy was significantly lower than in PD patients after L-DOPA therapy alone. These data suggest that cabergoline scavenges peroxynitrite induced by L-DOPA in patients with PD.

Perivascular infiltrate of memory lymphocytes and mature dendritic cells in MG thymomas.

In thymomas associated with myasthenia gravis (MG), the authors found that perivascular infiltrates of memory lymphocytes and mature dendritic cells (DCs) were more frequent in patients with early improvement after thymectomy than in patients without response to thymectomy. Although these findings may be limited to particular types of thymoma, thymectomy may interrupt the recruitment of mature DCs in thymus and export of activated T cells to extra-thymic tissues, thereby improving the disease.

Expression of cholesteryl ester transfer protein (CETP) in germinal centre B cells and their neoplastic counterparts.

AIMS: Cholesteryl ester transfer protein (CETP) is known to facilitate the transfer of lipids between plasma lipoproteins. Previous studies on human tissues have determined that the spleen contains large amounts of CETP mRNA, while the exact location of CETP in such organs remains unknown. In the present study, our aim was to locate CETP protein expression at the cellular level in human normal and neoplastic lymphoid organs. METHODS AND RESULTS: In-situ hybridization (ISH) and immunohistochemistry were applied to pathology specimens. A specific rabbit anti-CETP antibody was used for immunohistochemical analysis, together with another CETP-specific monoclonal antibody. A riboprobe for ISH was derived from CETP cDNA. Immunohistochemically, CETP was localized in germinal centre B cells and a proportion of marginal zone B cells. ISH showed that CETP mRNA was located mostly in the same areas. When 141 malignant lymphomas of various subtypes were studied, high expression of CETP, equivalent to that found in normal germinal centre B cells, was demonstrated in lymphoma subtypes that are currently regarded as the neoplastic counterparts of primarily germinal centre B cells. CONCLUSION: CETP localizes B cells in germinal centres, a proportion of post-germinal centre B cells and their neoplastic counterparts.

Myeloperoxidase-antineutrophil cytoplasmic antibody-associated sensorineural hearing loss.

A 36-year-old female with hyperthyroidism that had been treated with propilthiouracil (PTU) complained of tinnitus and hearing loss in both ears. She was treated with steroid administration by an otolaryngologist; however, hearing continued to fluctuate when the steroids were tapered. Laboratory evaluation revealed a decreased complement level and elevated levels of immunoglobulin M (IgM) and myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA). With the withdrawal of PTU and high-dose methylprednisolone, she had excellent return of right-sided hearing. In recent years, there have been many reports about MPO-ANCA-associated small vessel vasculitis. Although any organ may be affected by this disease, there are no reports about MPO-ANCA-associated progressive hearing loss without any other organ involvement. The present case suggests the possibility that inner ear blood flow impairment due to ANCA-associated small vessel vasculitis induces the so-called autoimmune sensorineural hearing loss.

Springtime pollinosis and oral allergy syndrome in Sapporo.

OBJECTIVE: The purpose of this present study was to investigate pollinosis in the spring and oral allergy syndrome (OAS) in Sapporo to utilize it for future treatment. MATERIALS AND METHODS: Of the patients referred to our out-patient clinic during April and May in 1999. all those that were suspected to have pollinosis were asked to fill in a questionnaire. A 101 patients (30 males and 71 females) with a mean age of 33 years (range 7-74 years) answered the questionnaire. In all, the patients specific IgE tests were performed. RESULTS: The most common allergen was birch, affecting 54 of 87 patients (62%). In 61% of patients with birch allergy, we observed fruit and vegetable allergy. Among them, apple was the most prevalent allergen (97%), followed by peach (67%), cherry (58%), pear (40%), plum (40%) and melon (33%). The sensitivity of skin prick test with commercial extract to apple was low (11%). CONCLUSION: Patients with birch pollen allergy had OAS much more frequently than ever reported in Japan, although OAS has not widely been known in Japan. Patients with birch pollen allergy should be informed about the possibility of hypersensitivity to certain fruits.

Development of a novel, weighted, quantifiable stroke scale: Japan stroke scale.

BACKGROUND AND PURPOSE: Several stroke scales are available for estimation of the severity of stroke, but none of them provides information regarding the relative weights of the observed variables. To define an integrated severity of stroke, we developed a quantifiable stroke scale with weighted variables that apply conjoint analysis to calculate the relative weight of each item. METHODS: We selected 10 variables (consciousness, language, neglect, hemianopsia, gaze, pupillary abnormality, facial palsy, plantar reflex, sensation, and weakness) based on the multivariate analysis of the Keio Stroke Patient Database Battery. The variables were categorized and evaluated for their distribution and sensitivity. The categorizations were then modified and rechecked. The procedure was repeated until the appropriate categorization was obtained from 198 patients. A temporary stroke scale without weight was then formulated, and the reliability of the scale was examined and revised with 80 new stroke patients. As a next step, 150 neurologists were asked to rank a set of 27 virtual patients, each with a different combination of variables, according to severity. From these rankings, conjoint analysis was used to derive utility scores (weights) for each factor level. RESULTS: The relative weights of each of the factors were as follows: consciousness 49.8%, language 9.9%, weakness of lower extremity 7.3%, pupillary abnormality 6.8%, gaze palsy 5.6%, weakness of arm 4.3%, weakness of hand 3.7%, neglect 3.7%, facial palsy 2.4%, plantar reflex 2.2%, hemianopsia 2.2%, and sensory impairment 2.1%. The total score for a patient could be calculated from the sum of the scores for each of the variables ranging from -0.38 to 27.86. Scoring of 100 patients with acute stroke was carried out, and the changes in scores were followed for validation. Longitudinal clinical monitoring of the patients correlated well with the scores in each patient. The interrater and intrarater reliabilities of the scale were excellent (weighted kappa 0.83; Cronbach's alpha 0.998). CONCLUSIONS: The Japan Stroke Scale is a parametric stroke scale that provides a quantitative measure of the severity of stroke. Each of the variables of the scale has a relative weight according to the severity of stroke. Reliability and responsiveness were proved to be excellent. The present data revealed a potentiality for the Japan Stroke Scale to be a universally accepted and reliable standardized system from the clinimetrical point of view.

P-ANCA-positive Wegener's granulomatosis presenting with hypertrophic pachymeningitis and multiple cranial neuropathies: case report and review of literature.

An autopsy case of hypertrophic pachymeningitis and multiple cranial neuropathies is reported. A 53-year-old woman with paraplegia and various neurological signs which developed over a 2 year period was diagnosed as having an epidural mass with thickened dura mater extending from the lower cervical to the thoracic spinal cord. In addition, bilateral episcleritis, blephaloptosis, and blindness of the right eye with various cranial nerve deficits were found to be caused by the mass lesions involving the paranasal sinuses, orbit, and the cavernous sinus. Perinuclear antineutrophil cytoplasmic antibody (p-ANCA) was positive, but cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) was negative by enzyme-linked immunosorbent assay. The partially removed epidural mass with hypertrophied dura mater and biopsy of the paranasal lesions showed chronic granulomatous inflammation with vasculitis. The remaining lesions resolved with steroid therapy with remarkable neurological improvement. The positive p-ANCA test, paranasal involvement, the report of a similar histopathological case and a review of the literature on granulomatous pachymeningitis suggest the presence of p-ANCA-positive Wegener's granulomatosis with central nervous system involvement characterized by hypertrophic pachymeningitis and/or multiple cranial neuropathies.

Risk factors accelerating cerebral degenerative changes, cognitive decline and dementia.

OBJECTIVES: Factors accelerating cerebral degenerative changes represent potentially modifiable risks for cognitive decline. Putative risk factors accelerating subtle cognitive decline and dementia were correlated with repeated measures of cerebral atrophy, CT densitometry, perfusions and cognitive testing among neurologically and cognitively normative ageing volunteers. METHODS: Two hundred and twenty-four normative subjects at increased risk for cognitive decline were admitted to the study. Mean entry age was 59. 5+/-15.8 years. Mean follow-up is 4.3+/-3.1 years. At follow-up, 22 developed subtle cognitive decline (deltaCCSE>/=-3), 19 became demented, eight with vascular type (VAD) and 11 with Alzheimer's type (DAT) and 183 remain cognitively unchanged. Standardized questionnaires, medical, neuropsychological, neurological and blood work examinations were obtained. Cerebral atrophy, tissue densities and perfusions were measured by xenon-enhanced CT. RESULTS: After age 60, cerebral atrophy, ventricular enlargement, polio- and leuko-araiosis geometrically increased as perfusions declined. Risk factors accelerating perfusional decline, cerebral atrophy, polio-araiosis and leuko-araiosis (thinning of grey-white matter densities) were: transient ischaemic attacks (TIAs), hypertension, smoking, hyperlipidemia, male gender. At age 71.5+/-11.9, subtle cognitive decline began, accelerated by TIAs, hypertension and heart disease. Leuko-araiosis began before cognitive decline. TIAs, hypertension and hyperlipidemia correlated with VAD. Excessive cortical perfusional decreases and cerebral atrophy correlated with cognitive decline. Family history of neurodegenerative disease correlated with DAT. CONCLUSION: TIAs, hypertension, hyperlipidemia, smoking and male gender accelerate cerebral degenerative changes, cognitive decline and dementia.

[Short interval change of 99mTc-ethyl cysteinate dimer single photon emission computed tomography in Wilson's disease].

We studied short interval change of cranial computed tomography (CT), magnetic resonance imaging (MRI) and 99mTc-ethyl cysteinate dimer single photon emission computed tomography (99mTc-ECD SPECT) in a case of Wilson's disease. Before treatment, CT scan showed low density changes in the bilateral thalamus and basal ganglia, and MRI demonstrated high intensity in same lesions. 99mTc-ECD SPECT study revealed a hypoperfusion in bilateral thalamus. After 2 months under D-penicillamine therapy, neurological findings had improvement. Hypoperfusion in the thalamus with 99mTc-ECD SPECT significantly improved, whereas abnormal findings of CT scan and MRI persisted. 99mTc-ECD SPECT study may be useful for the planning of the treatment of Wilson's disease.

[Clinicopathological investigation of malignant alteration in nasal and paranasal sinus papilloma using flow cytometric DNA ploidy].

Among tumors of the head and neck, nasal and paranasal sinus papilloma is a relatively rare benign tumor. However, it is different from other benign nasal and paranasal tumors, in histological morphology, and in higher probabilities of recurrence, complication with malignant tumor, and malignant alteration. In this study, we examined clinically and pathologically 30 patients with nasal and paranasal sinus papilloma who underwent operations in our department between 1975 and 1994. The tumor occurred in the opening of the maxillary sinus in 19 patients and in the nasal septum in 7 patients. Destruction of bone was observed in 12 patients. Pathological examination revealed inverted papilloma in 17 patients, exophytic papilloma in 13 patients, and atypia in 4 patients. Recurrence was observed in 9 patients, and malignant alteration was observed in 5 patients. Using paraffin sections, aneuploidy was assessed by flow cytometric DNA ploidy. Diploid in 25 cases (83.3%) and aneuploid in 5 cases (16.7%) were observed. Risk factors of malignant alteration in nasal and paranasal papilloma are considered to be 1) developmental morphology, 2) destruction of bones, 3) atypia in pathology, 4) recurrence before progression to malignancy, and 5) the presence of aneuploidy. The 5 patients in whom malignant alteration was observed each showed 4 of the 5 risk factors, suggesting that malignant alteration is most likely to occur in nasal and paranasal papilloma that show 4 or 5 risk factors. The period up to malignant alteration varies; in one patient, it was more than 10 years. Therefore, follow-up observation over a long period is required.

Age-related cerebrovascular disease alters the symptomatic course of migraine.

Migraine headaches usually decrease in frequency and severity and often cease during advancing age. Occasionally, migraineurs report late-life migrainous accompaniments, i.e., auras without headache, particularly when typical migraine attacks terminate or diminish following major or minor strokes, at which time the auras may become atypical. Clinical observations such as these suggest that degenerative cerebrovascular changes accompanying aging may modify the course of migraine headaches particularly those with aura. To test this hypothesis, we quantitated age-related changes in cerebral vasodilator capacitance by measuring local cerebral blood flow utilizing xenon contrast computed tomography (CT) scanning before and after oral administration of the pharmacological cerebral vasodilator, acetazolamide (Diamox). Measurements were compared among 27 normal volunteers without headache (aged 24-94 years; mean age 61.1 +/- 17.6) and 37 carefully categorized groups of migraine patients (aged 27-83 years; mean age 59.4 +/- 12.4). The normals comprised Group A. Migraineurs were divided into two subgroups: Group B consisted of 27 migraineurs with and without aura who continued to suffer from incapacitating and frequent headaches and Group C consisted of 10 migraineurs who no longer suffered from severe and frequent headaches, two of whom still complained of atypical auras of the "late-life migrainous accompaniments" type. Cerebral vasodilator capacitance significantly declined with advancing age among normals and the two groups of migraineurs, confirming the development of age-related cerebrovascular diseases. Global CBF increases after Diamox in Group B (with persistent and severe migraine), were significantly greater compared with normals without headache, and with Group C consisting of migraineurs whose headaches had decreased, subsided, or become replaced by late-life migrainous accompaniments (Group C). Results establish that cerebrovasodilator capacitance declines with advancing age, probably due to progressive cerebral atherosclerosis, since these declines were accentuated by risk factors for stroke, particularly TIAs or documented lacunar infarcts by CT. Progressive impairments of cerebral vasodilator capacitance among migraineurs were associated with: (i) reductions in frequency and severity of migrainous cephalalgia and (ii) appearance of late-life migrainous accompaniments.

Risk factors for cerebral degenerative changes and dementia.

It is concluded that the most important determinants for cerebral neurodegenerative changes and cognitive decline during aging are neuronal shrinkage and/or loss, which are accelerated by certain risk factors: e.g. TIAs, hypertension, heart disease, hyperlipidemia, smoking, heavy alcohol consumption, male gender, low educational status, family history of cerebrovascular disease and absence of estrogen replacement therapy among women. Some of these risk factors are remediable by therapeutic interventions, including prevention of TIAs and medications that control hypertension, heart disease, hyperlipidemia and estrogen replacement in postmenopausal women, as well as abstention from abuse of tobacco and alcohol. Cerebral neurodegenerative changes measured by neuroimaging appear to be premorbid markers for depleted neuronal and synaptic reserves which predispose to the onset of dementias of both VAD and DAT types. Normal subjects at risk for cognitive decline include those with TIAs, hypertension and heart disease since these risk factors measurably accelerate cerebral atrophy, ventricular enlargement, leukoaraiosis, and decline in cortical perfusion.

Vasodilator responses to acetazolamide tested in subtypes of vascular dementia.

OBJECTIVES: Thirty seven vascular dementia (VAD) patients were categorized into eight subtypes based on clinical, radiological, and pathogenetic features. Cerebral vasodilator responses to acetazolamide were then compared with age-matched normal controls and stroke patients without dementia. METHODS: VAD results were compared with 42 normals and 19 cognitively intact stroke patients. Regional cerebral vasodilator responses were quantitated utilizing xenon contrasted computed tomography measures of local cerebral blood flow (LCBF) before and after oral administration of acetazolamide. LCBF changes (DeltaLCBF) before and after acetazolamide were calculated within cortical and subcortical, gray and white matter. Clinical VAD subtypes were: type 1, multi-infarct dementia (MID); type 2, strategically placed infarcts; type 3, subcortical lacunar infarcts; type 4, Binswanger's subcortical arteriosclerotic leukoencephalopathy; type 5, subcortical infarctions due to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), inflammatory angitis, or antiphospholipid antibodies; type 6, admixtures of above types; type 7, cerebral hemorrhagic lesions; and type 8, VAD combined with Alzheimer's disease (DAT). The group with subcortical VAD comprised types 3-5. The group with cortical VAD comprised the remainder (types 1, 2, and 6-8). Cerebral vasodilator responses were also compared between these two main groups. RESULTS: Cerebral vasodilator responses identified differences between the two main groups of VAD patients, those with cortical and those with subcortical dementia. Leukoaraiosis was measurably greater in subcortical VAD compared with cortical VAD. Among subcortical VAD patients, cortical LCBF increases after administration of acetazolamide were greater compared with cortical VAD and with normal controls. CONCLUSIONS: Cognitive impairments in subcortical VAD are attributable to cortical disconnection syndromes. This concept is supported by reduced perfusion in deactivated cortex. In patients with subcortical VAD, deactivated cortical LCBF becomes promptly activated by acetazolamide resulting in marked cortical LCBF increases. Leukoaraiosis is greater among VAD patients and leukoaraiosis contributes to cortical disconnections, confirmed by excessive cortical vasodilator responses to acetazolamide.