Ville Leinonen

The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae

The amyloid β-peptide (Aβ) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by Aβ and accumulation of Aβ has been detected in mitochondria. Because Aβ is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial Aβ uptake. Our results from rat mitochondria show that Aβ is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed Aβ association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Aβ to mitochondrial cristae. A similar distribution pattern of Aβ in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for Aβ in mitochondria and demonstrate both in vitro and in vivo that Aβ is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied Aβ can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of Aβ, a peptide considered to be of major significance in Alzheimers disease.

Assessment of β-Amyloid in a Frontal Cortical Brain Biopsy Specimen and by Positron Emission Tomography With Carbon 11–Labeled Pittsburgh Compound B

OBJECTIVE To compare carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) findings in patients with and without Alzheimer disease lesions in frontal cortical biopsy specimens. DESIGN Cross-sectional study of [11C]PiB PET findings in patients with or without beta-amyloid (Abeta) aggregates in frontal cortical biopsy specimens. SETTING Two university hospitals in Finland. Patients Ten patients who had undergone intraventricular pressure monitoring with a frontal cortical biopsy (evaluated for Abeta aggregates and hyperphosphorylated tau) for suspected normal-pressure hydrocephalus. INTERVENTIONS [11C]PiB PET and evaluation for cognitive impairment using a battery of neuropsychological tests. MAIN OUTCOME MEASURES Immunohistochemical evaluation for Abeta aggregates and hyperphosphorylated tau in the frontal cortical biopsy specimen and [11C]PiB PET. RESULTS In patients with Abeta aggregates in the frontal cortical biopsy specimen, PET imaging revealed higher [11C]PiB uptake (P < .05) in the frontal, parietal, and lateral temporal cortices and in the striatum as compared with the patients without frontal Abeta deposits. CONCLUSIONS Our study supports the use of noninvasive [11C]PiB PET in the assessment of Abeta deposition in the brain. Large prospective studies are required to verify whether [11C]PiB PET will be a diagnostic aid, particularly in early Alzheimer disease.

Back and hip extensor activities during trunk flexion/extension: Effects of low back pain and rehabilitation

OBJECTIVE To compare lumbar paraspinal, gluteus maximus, and biceps femoris muscle function during sagittal trunk flexion and extension in patients with chronic low back pain and healthy control subjects, and to assess the influence of rehabilitation in the back pain patients. DESIGN A cross-sectional study comparing chronic low back pain patients and healthy controls, and a prospective follow-up in back pain patients during rehabilitation. SETTING Physical medicine and rehabilitation clinic. SUBJECTS Nineteen women with chronic low back pain, and 19 women without pain (controls). INTERVENTION Five-week active outpatient rehabilitation (1 hour three times a week) guided by a physiotherapist, followed by 5-week self-motivated exercise at home. OUTCOME MEASURES Subjects performed sagittal trunk flexion and extension while surface electromyogram was bilaterally recorded of paraspinal (L1-L2 level), gluteus maximus, and biceps femoris muscles. The muscle activity was assessed from the average electromyogram and the relative muscle activation onsets and their duration were calculated. RESULTS During early flexion, lumbar paraspinal and biceps femoris were activated simultaneously before gluteus maximus. At the end of flexion and during extension all investigated muscles were activated and relaxed in order. Lumbar paraspinal and biceps femoris muscles were activated in a similar order in low back pain patients and healthy controls during flexion and extension. However, the duration of gluteus maximus activity was shorter in the back pain patients than in controls during the trunk flexion (p<.05), and it ended earlier during extension. Active rehabilitation did not change the muscle activities of lumbar paraspinal and biceps femoris in the back pain patients, but in the measurements after rehabilitation the onset of gluteus maximus activity occurred later in flexion and earlier in extension. CONCLUSIONS The activity of the gluteus maximus muscle during the flexion-extension cycle was reduced in patients with chronic low back pain. The gluteal muscles should be taken into consideration in the rehabilitation of these patients.

CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings

Objective: To assess the relationship between Alzheimer disease (AD)–related pathologic changes in frontal cortical brain biopsy and AD biomarkers in ventricular vs lumbar CSF, and to evaluate the relationships of AD biomarkers in CSF and cortical biopsy with the final clinical diagnosis of AD. Methods: In 182 patients with presumed normal pressure hydrocephalus (152 with known APOE carrier status), Aβ plaques and tau in the cortical brain biopsies were correlated with the ventricular and lumbar CSF Aβ42, total tau, and p-tau levels measured by ELISA. In a median follow-up of 2.0 years, 51 patients developed AD dementia. Results: The patients with Aβ plaques in the cortical biopsy had lower (p = 0.009) CSF Aβ42 levels than those with no Aβ plaques. The patients with tau in the cortical biopsy had lower (p = 0.014) Aβ42 but higher (p = 0.015) p-tau 181 in CSF as compared to those with no tau in the cortical biopsy. The patients with amyloid + tau + biopsies had the lowest Aβ42 and highest tau and p-tau 181 levels in CSF. The Aβ42 levels were lower and the tau and p-tau 181 higher in the ventricular vs corresponding lumbar CSF samples. In multivariate analysis, the presence of cortical Aβ was independently predicted by the APOE ϵ4 carrier status and age but not by CSF Aβ42 or tau levels. Conclusions: Amyloid plaques and hyperphosphorylated tau in cortical brain biopsies are reflected by low CSF Aβ42 and high CSF tau and p-tau levels, respectively.

Lumbar paraspinal muscle function, perception of lumbar position, and postural control in disc herniation-related back pain.

Study Design. A follow-up study evaluating postural control, lumbar movement perception, and paraspinal muscle reflexes in disc herniation-related chronic low back pain (LBP) before and after discectomy. Objectives. To assess the effect of discectomy on postural control, lumbar perception, and reflex activation of paraspinal muscles during sudden upper limb loading. Summary of Background Data. Impaired muscle function, postural control, and lumbar proprioception have been observed in LBP. However, they have not been studied in sciatica patients after surgery. Methods. The study included 20 patients selected for an operation for chronic LBP caused by disc herniation and 15 controls without chronic LBP. The paraspinal muscle responses for upper limb loading during unexpected and expected conditions were measured by surface electromyography. The ability to sense lumbar rotation was assessed in a previously validated motorized trunk rotation unit in the seated position. The postural control was measured with a vertical force platform. Pain, disability, and depression scores were recorded. Results. Patients had poorer lumbar perception (P = 0.012) and postural control (P < 0.05) than did healthy controls. The postural control remained unchanged, but lumbar perception (P = 0.054) and the lumbar feed-forward control (P = 0.043) improved after the surgery. Conclusions. The results demonstrate impaired lumbar proprioception and postural control in sciatica patients. During short-term follow-up after operative treatment, postural control does not seem to change, but impaired lumbar proprioception and feed-forward control of paraspinal muscles seem to recover.

Influence of comorbidities in idiopathic normal pressure hydrocephalus — research and clinical care. A report of the ISHCSF task force on comorbidities in INPH

Idiopathic normal pressure hydrocephalus (INPH) is a syndrome of ventriculomegaly, gait impairment, cognitive decline and incontinence that occurs in an elderly population prone to many types of comorbidities. Identification of the comorbidities is thus an important part of the clinical management of INPH patients. In 2011, a task force was appointed by the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders (ISHCSF) with the objective to compile an evidence-based expert analysis of what we know and what we need to know regarding comorbidities in INPH. This article is the final report of the task force. The expert panel conducted a comprehensive review of the literature. After weighing the evidence, the various proposals were discussed and the final document was approved by all the task force members and represents a consensus of expert opinions. Recommendations regarding the following topics are given: I. Musculoskeletal conditions; II. Urinary problems; III. Vascular disease including risk factors, Binswanger disease, and white matter hyperintensities; IV. Mild cognitive impairment and Alzheimer disease including biopsies; V. Other dementias (frontotemporal dementia, Lewy body, Parkinson); VI. Psychiatric and behavioral disorders; VII. Brain imaging; VIII. How to investigate and quantify. The task force concluded that comorbidity can be an important predictor of prognosis and post-operative outcome in INPH. Reported differences in outcomes among various INPH cohorts may be partly explained by variation in the rate and types of comorbidities at different hydrocephalus centers. Identification of comorbidities should thus be a central part of the clinical management of INPH where a detailed history, physical examination, and targeted investigations are the basis for diagnosis and grading. Future INPH research should focus on the contribution of comorbidity to overall morbidity, mortality and long-term outcomes.

Amyloid and tau proteins in cortical brain biopsy and Alzheimer's disease

Amyloid‐β(Aβ) aggregates are presumed to be found in the brain at an early stage of Alzheimers disease (AD) but have seldom been assessed by brain biopsy during life in often elderly patients.

Poor Cognitive Outcome in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus

BACKGROUND Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce. OBJECTIVE To elucidate the long-term cognitive condition of shunt-responsive iNPH patients. METHODS The follow-up data (Kuopio University Hospital NPH Registry) of 146 patients diagnosed with iNPH by clinical and radiological examination, 24-hour intraventricular pressure monitoring, frontal cortical biopsy, and response to the shunt were analyzed for signs of dementia. The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, and specified memory disorder criteria were used. Median follow-up was 4.8 years. RESULTS At the end of follow-up, 117 (80%) of the 146 iNPH patients had cognitive decline and 67 (46%) had clinical dementia. The most common clinical diagnoses were Alzheimer disease and vascular dementia. In multivariate analysis of the 146 iNPH patients, memory deficit as a first symptom before shunt (odds ratio [OR] 18.3; 95% confidence interval [CI] 1.9-175), male sex (OR 3.29; 95% CI 1.11-9.73), age (OR 1.17 year; 95% CI 1.07-1.28), and follow-up time (OR 1.20 year; 95% CI 1.02-1.40) predicted dementia. Interestingly, 8 (5%) iNPH patients had dementia without any signs of other neurodegenerative diseases in clinical, neuroradiological, or brain biopsy evaluation. These patients initially presented a full triad of symptoms, with gait disturbance being the most frequent initial symptom followed by deterioration in cognition. CONCLUSION The novel findings were (a) a significant risk of dementia in iNPH initially responsive to cerebrospinal fluid shunt, (b) cognitive impairment most commonly due to iNPH-related dementia followed by concurrent degenerative brain disease, and (c) a subgroup with dementia related to iNPH without comorbidities.

Impaired Lumbar Movement Perception in Association With Postural Stability and Motor- and Somatosensory-Evoked Potentials in Lumbar Spinal Stenosis

Study Design. A descriptive study of the associations between different neurophysiologic findings in patients with lumbar spinal stenosis. Objectives. To evaluate the ability to sense a change in lumbar position and the associations between lumbar movement perception, postural stability, and motor-evoked potentials and somatosensory-evoked potentials. Summary of Background Data. Patients with low back pain have impaired postural control and impaired lumbar proprioception. Altered motor-evoked potentials and somatosensory-evoked potentials have been often observed in lumbar spinal stenosis. Methods. The study included 26 patients with clinically and radiologically diagnosed lumbar spinal stenosis. Their ability to sense lumbar rotation was assessed in a previously validated motorized trunk rotation unit in the seated position. The abilities to indicate the movement direction and the movement magnitude were used as indexes of the ability to sense the lumbar rotatory movement. The postural stability was measured with a vertical force platform. The motor-evoked potentials were elicited by transcranial and lumbar stimulation and recorded from anterior tibialis muscles. The somatosensory-evoked potentials were elicited by transcutaneous electrical stimulation of the tibial nerve at the ankle. Results. Twenty patients (76.9%;P = 0.006) reported the wrong movement direction. Furthermore, the patients consistently localized the movement sensation in their shoulders instead of the lumbar region. The altered motor-evoked potentials and somatosensory-evoked potentials were observed in 11 and 16 patients, respectively. Abnormal motor-evoked potentials had inconsistent associations with impaired movement perception and postural stability and abnormal somatosensory-evoked potentials had no associations with other findings. Conclusions. Many patients with lumbar spinal stenosis have difficulties in sensing the lumbar rotational movement, which may indicate impaired proprioceptive abilities. Abnormal motor-evoked potentials and somatosensory-evoked potentials are also frequent in lumbar spinal stenosis but do not necessarily occur in the same patients as the abnormal ability to sense trunk movement. These new findings add to our understanding of the pathophysiology of lumbar spinal stenosis.

Post-mortem findings in 10 patients with presumed normal-pressure hydrocephalus and review of the literature.

V. Leinonen, A. M. Koivisto, S. Savolainen, J. Rummukainen, A. Sutela, R. Vanninen, J. E. Jääskeläinen, H. Soininen and I. Alafuzoff (2012) Neuropathology and Applied Neurobiology38, 72–86