Sakari Savolainen

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.

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.

Decreased strength and mobility in patients after anterior cervical diskectomy compared with healthy subjects.

OBJECTIVE To evaluate whether patients acquired normal physical function after cervical disk prolapse and surgery compared with healthy matched controls. DESIGN Cross-sectional study. SETTING Hospital in central Finland. PARTICIPANTS Fifty-three patients with cervical diskectomy and 53 healthy matched controls. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Postoperative physical function was studied by measuring muscle strength and range of motion (ROM) values of the neck and grip strength. Disability was assessed by the neck and shoulder pain index and by the Oswestry index, mood by the Short Depression Inventory; and pain on a visual analog scale (VAS). RESULTS Most patients recovered well after the operation. Forty-three percent of the patients still experienced moderate or high pain (VAS score, >30mm). Subjective pain and disability were associated with decreased neck movement and strength. Both ROM and cervical muscle strength values were significantly lower (P<.001) in all the measured directions in cervical disk surgery patients compared with healthy controls. ROM was mostly confined in extension (25%). Muscle strength of the neck was mostly confined in both rotation directions (38%). No statistically significant difference in grip strength was found between the groups. CONCLUSION The loss of muscle strength and ROM is clearly visible postoperatively and thus the effectiveness of the early identification and rehabilitation of these deficits merits further studies.

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

Depression and associated factors in patients with lumbar spinal stenosis

Purpose. To investigate the prevalence of depression and associated factors in patients (n = 100) with lumbar spinal stenosis selected for surgical treatment. Method. Depression was assessed with the 21-item Beck Depression Inventory. Psychological well-being was assessed with Life Satisfaction Scale, Toronto Alexithymia Scale and Sense of Coherence Scale. Physical functioning and pain were assessed with the Oswestry disability index, the questionnaire devised by Stucki and the Visual Analogue Scale. All questionnaires were administered before surgical treatment of lumbar spinal stenosis. Results. Twenty percent of the patients with LSS were found to have clinically important depression. In univariate analyses, subjective disability measured with the Oswestry disability index, low sense of coherence and poor life satisfaction were common in depressed patients. In the multiple logistic regression analyses, being dissatisfied with life was associated with depression. When sense of coherence score was included in the model, then only low sense of coherence was independently associated with depression. Neither socio-demographic nor pain-related factors associated with depression. Conclusions. Clinically important depression is rather common among preoperative patients with lumbar spinal stenosis. The factors associated with depression are subjective disability of everyday living and decreased life satisfaction. A low sense of coherence is an important correlate of depression. The results underline the importance of assessing depression in clinical practice dealing with these patients.

Cerebrospinal fluid biomarker and brain biopsy findings in idiopathic normal pressure hydrocephalus

Background The significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimers disease (AD) is unknown. Objective To investigate the role of soluble APP (sAPP) and amyloid beta (Aβ) isoforms, proinflammatory cytokines, and biomarkers of neuronal damage in the cerebrospinal fluid (CSF) in relation to brain biopsy Aβ and hyperphosphorylated tau (HPτ) findings. Methods The study population comprised 102 patients with possible NPH with cortical brain biopsies, ventricular and lumbar CSF samples, and DNA available. The final clinical diagnoses were: 53 iNPH (91% shunt-responders), 26 AD (10 mixed iNPH+AD), and 23 others. Biopsy samples were immunostained against Aβ and HPτ. CSF levels of AD-related biomarkers (Aβ42, p-tau, total tau), non-AD-related Aβ isoforms (Aβ38, Aβ40), sAPP isoforms (sAPPα, sAPPβ), proinflammatory cytokines (several interleukins (IL), interferon-gamma, monocyte chemoattractant protein-1, tumor necrosis factor-alpha) and biomarkers of neuronal damage (neurofilament light and myelin basic protein) were measured. All patients were genotyped for APOE. Results Lumbar CSF levels of sAPPα were lower (p<0.05) in patients with shunt-responsive iNPH compared to non-iNPH patients. sAPPβ showed a similar trend (p = 0.06). CSF sAPP isoform levels showed no association to Aβ or HPτ in the brain biopsy. Quantified Aβ load in the brain biopsy showed a negative correlation with CSF levels of Aβ42 in ventricular (r = −0.295, p = 0.003) and lumbar (r = −0.356, p = 0.01) samples, while the levels of Aβ38 and Aβ40 showed no correlation. CSF levels of proinflammatory cytokines and biomarkers of neuronal damage did not associate to the brain biopsy findings, diagnosis, or shunt response. Higher lumbar/ventricular CSF IL-8 ratios (p<0.001) were seen in lumbar samples collected after ventriculostomy compared to the samples collected before the procedure. Conclusions The role of sAPP isoforms in iNPH seems to be independent from the amyloid cascade. No neuroinflammatory background was observed in iNPH or AD.

Somatic comorbidity and younger age are associated with life dissatisfaction among patients with lumbar spinal stenosis before surgical treatment

The objective of the study was to examine self-reported life satisfaction and associated factors in patients (n=100) with lumbar spinal stenosis (LSS) in secondary care level, selected for surgical treatment. Life satisfaction was assessed with the four-item Life Satisfaction scale. Depression was assessed with a 21-item Beck Depression Inventory (BDI). Psychological well-being was assessed with Toronto Alexithymia Scale and Sense of Coherence Scale. LSS related physical functioning and pain were assessed with Oswestry disability index, Stucki questionnaire, Visual Analogue Scale and pain drawings. All questionnaires were administered before surgical treatment of LSS. Results showed that 25% of the patients with LSS were found to be dissatisfied with life. In a univariate analysis, smoking, elevated subjective disability scores and extensive markings in the pain drawings were more common in the dissatisfied patients. The dissatisfied patients also showed lower coping resources, elevated alexithymia and depression scores, and were more often depressed. In multiple logistic regression analyses, only younger age and somatic comorbidity were associated with life dissatisfaction. This association remained significant even when the BDI score was added into the model. No other significant associations emerged. In conclusion, life dissatisfaction was rather common among preoperative LSS patients. Pain and constraints on everyday functioning were important correlates of life dissatisfaction. However, only younger age and somatic comorbidity were independently associated with life dissatisfaction. These results emphasize the importance of recognizing and assessing the effect of coexisting medical conditions and they need to be addressed in any treatment program.

Cortical Brain Biopsy in Long-Term Prognostication of 468 Patients with Possible Normal Pressure Hydrocephalus

Normal pressure hydrocephalus (NPH) can be alleviated by cerebrospinal fluid shunting but the differential diagnosis and patient selection are challenging. Intraventricular intracranial pressure monitoring as part of the diagnostic workup as well as shunting enable to obtain cortical brain biopsies to detect amyloid-β (Aβ) and hyperphosphorylated tau (HPτ), the hallmark lesions of Alzheimer’s disease (AD). In possible NPH, Aβ alone indicates an increased risk of AD and when present with HPτ probable AD, but the effect of those brain lesions on survival is not known. The aim of this study was to evaluate the predictive value of brain biopsy for the long-term outcome of possible NPH. Between 1991 and 2006, the Neurosurgery Department of the Kuopio University Hospital evaluated 468 patients for possible NPH by intraventricular intracranial pressure monitoring and frontal cortical brain biopsy immunostained against Aβ and HPτ. All patients were followed up until the end of 2008 (n = 201) or death (n = 267) with a median follow-up of 4.6 years (range 0–17). Logistic regression analysis with Cox models was applied. Out of the 468 cases, Aβ was detected in 197 (42%) cortical biopsies, and together with HPτ in 44 (9%). Aβ alone indicated increased risk of AD and with HPτ probable AD, but it did not affect survival. Vascular aetiology was the most frequent cause of death. Cortical biopsy findings indicate that NPH is at present a heterogeneous syndrome and has notable overlapping with AD. Brain biopsy did not predict survival but may open a novel research window to study the pathobiology of neurodegeneration.

APOE4 predicts amyloid-β in cortical brain biopsy but not idiopathic normal pressure hydrocephalus

Objective To investigate the association of apolipoprotein E (APOE) genotype, especially the APOE4 allele, to (1) idiopathic normal pressure hydrocephalus (iNPH) and (2) amyloid-β (Aβ) plaques in cortical brain biopsies of presumed NPH patients with and without a final clinical diagnosis of Alzheimers disease (AD). Methods 202 patients with presumed NPH were evaluated by intraventricular pressure monitoring and frontal cortical biopsy immunostained against Aβ (134 semiquantified by Aβ plaques/mm2). The 202 patients and 687 cognitively healthy individuals were genotyped for APOE. The final clinical diagnoses in a median follow-up of 3.9 years were: 113 iNPH (94 shunt responsive, 16 shunt non-responsive, three not shunted); 36 AD (12 mixed iNPH + AD); 53 others. Results The APOE genotypes distributed similarly in the 94 shunt responsive and 16 non-responsive iNPH patients and healthy controls. In multivariate analysis, the APOE4 allele correlated independently with Aβ plaques in the cortical biopsies (OR 8.7, 95% CI 3.6 to 20, p<0.001). The APOE4 allele in presumed NPH predicted later AD as follows: sensitivity 61%; specificity 77%; positive predictive value 37%; negative predictive value 90%. Conclusion In presumed NPH patients, APOE4 associates independently with the presence of Aβ plaques in the frontal cortical biopsy. APOE4 is not a risk factor for iNPH and does not predict the response to shunt. Our data further support the view that the iNPH syndrome is a distinct dementing disease. Trial registration number Kuopio NPH Registry (http://www.uef.fi/nph)