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Alzheimer's Disease Neuropathological Change and neuronal and glial alterations in patients with idiopathic Normal Pressure Hydrocephalus
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.ORCID-id: 0000-0003-1043-5385
2021 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Alzheimer’s disease Neuropathological Change (ADNC), i.e. amyloid β (Aβ) and hyperphosphorylated τ (HPτ), is seen in excess in the brains of subjects with AD. Idiopathic Normal Pressure Hydrocephalus (iNPH) lacks defined hallmark lesions, affects the elderly and leads to cognitive impairment, gait disturbance and urinary incontinence that can be treated with a ventriculoperitoneal shunt (VPS). A few centres around the world have obtained a brain biopsy from the area of VPS. It has been reported that the presence of ADNC in the biopsy is associated with progression to AD.

We confirm that majority of iNPH subjects display ADNC, and the ADNC increases in extent with age, in line with AD. The HPτ pathology is sparse in majority of cases. We observed remarkable neuronal survival and loss of matrix/synapses in subjects with iNPH (paper III).

When studying subjects with notable Aβ pathology (paper IV), we observed a stepwise increase of pyroglutamylated Aβ (pyAβ) and phosphorylated Aβ variants in iNPH. These two Aβ variants are associated with symptomatic AD and correlate with HPτ pathology. The pyAβ in the frontal cortex is a predictive marker for AD. Thus, notable Aβ pathology in presence of HPτ in iNPH is suggestive of a moderate level of ADNC.  

When assessing changes in the extent of pathology occurring during 21 months in a frontal cortex of a subject with iNPH and AD (paper II), HPτ pathology increased in parallel with neuronal and synaptic loss, whereas Aβ pathology and astroglial activity were stable over time. In contrast, we observed reduction of microglial markers, which might explain why anti-inflammatory treatment is effective only at an early stage of AD.

When assessing brain tissue, the section thickness must be standardised, as it affects the staining outcome and diagnosis (paper I).

In conclusion, we have demonstrated a progressive neurodegeneration of ADNC type in a population of iNPH subjects, mimicking what is seen in subjects with AD. A brain biopsy obtained from subjects with iNPH should be obligatory. This is because when ADNC is present in the biopsy, representing prodromal AD, contact with memory clinic should be initiated.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2021. , s. 76
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1719
Nyckelord [en]
idiopathic Normal Pressure Hydrocephalus, Alzheimer’s disease, amyloid β, hyperphosphorylated τ
Nationell ämneskategori
Annan klinisk medicin
Forskningsämne
Patologi
Identifikatorer
URN: urn:nbn:se:uu:diva-433963ISBN: 978-91-513-1132-6 (tryckt)OAI: oai:DiVA.org:uu-433963DiVA, id: diva2:1525517
Disputation
2021-03-27, Rudbecksalen, Rudbeckslaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2021-03-05 Skapad: 2021-02-03 Senast uppdaterad: 2021-03-29
Delarbeten
1. Characteristics of the tissue section that influence the staining outcome in immunohistochemistry
Öppna denna publikation i ny flik eller fönster >>Characteristics of the tissue section that influence the staining outcome in immunohistochemistry
2019 (Engelska)Ingår i: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 151, nr 1, s. 91-96Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Immunohistochemistry (IHC) is influenced by several factors such as cold ischemia time, fixative, fixation time, paraffin, storage time, antibody, antigen retrieval technique and detection systems. In the setting of post-mortem tissue, not only post-mortem delay, but also agonal state is of interest. Here, we assessed an additional variable, i.e., the thickness of the section, and noted that this variable also influenced the IHC outcome. This is of significance when the extent of labelling is a parameter to be assessed, for example when assigning a stage or grade of a disease. Furthermore, when assessing brain tissue with neurons, soma measuring from 4 to 100 µm, various cellular compartments composed of different proteins are localised in sections measuring 4 or 7 µm. Thus, what is seen in a 7-µm-thick section might be lacking in a 4-µm-thick section. Lack of information regarding the molecular size of commercial antibodies is also disturbing as this parameter might influence the distribution of the molecule in the three-dimensional section. The choice of antibody to be used and the staining methodology have been acknowledged being of significance for IHC outcome; however, neither sections thickness or the molecular weight has been discussed sufficiently. IHC has been shown to be an unpredictable technique used for assessment of tissue. This emphasises the need for detailed methodological descriptions in publications, the need to acknowledge and to harmonize all eventual pitfalls related to this methodology.

Nyckelord
Extent of staining, Immunohistochemistry, Pitfalls, Thickness of a section
Nationell ämneskategori
Klinisk laboratoriemedicin
Forskningsämne
Patologi
Identifikatorer
urn:nbn:se:uu:diva-372540 (URN)10.1007/s00418-018-1742-1 (DOI)000455442800009 ()30357509 (PubMedID)
Forskningsfinansiär
Hans-Gabriel och Alice Trolle-Wachtmeisters stiftelse för medicinsk forskning
Tillgänglig från: 2019-01-07 Skapad: 2019-01-07 Senast uppdaterad: 2021-02-03Bibliografiskt granskad
2. Progression of Alzheimer's Disease-Related Pathology and Cell Counts in a Patient with Idiopathic Normal Pressure Hydrocephalus
Öppna denna publikation i ny flik eller fönster >>Progression of Alzheimer's Disease-Related Pathology and Cell Counts in a Patient with Idiopathic Normal Pressure Hydrocephalus
2018 (Engelska)Ingår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, nr 4, s. 1451-1461Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We had an opportunity to assess the change observed in the brain regarding Alzheimer’s disease (AD)-related alterations, cell count, and inflammation that took place during a period of 21 months in a subject with a definite diagnosis of AD and idiopathic Normal Pressure Hydrocephalus (iNPH). Four neuronal markers, i.e., synaptophysin, microtubule associated protein 2, non-phosphorylated neurofilament H (SMI32), and embryonic lethal abnormal visual system proteins 3/4 HuC/HuD (HuC/HuD); three microglial markers CD68, Human Leucocytic Antigen DR, ionized calcium-binding adaptor molecule 1, glial fibrillary acidic protein (GFAP); and AD-related markers, hyperphosphorylated τ (HPτ) and amyloid-β (Aβ, Aβ40, Aβ42) were assessed. Morphometrically assessed immunoreactivity of all neuronal and all microglial markers and Aβ42 decreased parallel with an increase in the HPτ in the frontal cortex. The expression of GFAP was stable with time. The first sample was obtained during the therapeutic shunting procedure for iNPH, and the second sample was obtained postmortem. Negligible reactive changes were observed surrounding the shunt channel. In conclusion, in the late stage of AD with time, a neuronal loss, increase in the HPτ, and decrease in Aβ42 and microglia was observed, whereas the expression of GFAP was rather stable. The observations described here suggest that when a brain biopsy has been obtained from an adult subject with iNPH, the assessment of postmortem brain is of major significance.

Nyckelord
Amyloid-beta, astrocytes, hyperphosphorylated tau, idiopathic normal pressure hydrocephalus, immunohistochemistry, microglia, neurons
Nationell ämneskategori
Neurovetenskaper Neurologi Klinisk laboratoriemedicin
Forskningsämne
Patologi
Identifikatorer
urn:nbn:se:uu:diva-346377 (URN)10.3233/JAD-170446 (DOI)000423364400018 ()29376849 (PubMedID)
Tillgänglig från: 2018-03-23 Skapad: 2018-03-23 Senast uppdaterad: 2021-02-03Bibliografiskt granskad
3. Alzheimer's disease neuropathological change and loss of matrix/neuropil in patients with idiopathic Normal Pressure Hydrocephalus, a model of Alzheimer's disease
Öppna denna publikation i ny flik eller fönster >>Alzheimer's disease neuropathological change and loss of matrix/neuropil in patients with idiopathic Normal Pressure Hydrocephalus, a model of Alzheimer's disease
2019 (Engelska)Ingår i: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 7, artikel-id 98Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Here, we assessed unique brain tissue samples, obtained from living subjects with idiopathic Normal Pressure Hydrocephalus (iNPH). Our cohort of 95 subjects with age ranging from 75 to 79 years, displayed a high prevalence of beta-amyloid (A beta) and hyperphosphorylated t (HPt) pathology (63 and 61%, respectively) in a frontal cortex biopsy obtained during shunt operation. These lesions, i.e., Alzheimer's Disease Neuropathologic Change (ADNC), increased within 5 years and were more frequent in females. The extent of HPt pathology was sparse, primarily seen as neurites and stained dots. Noteworthy, concomitant pathology was seen in 49% of the whole cohort, indicating a severity of ADNC corresponding to a low/intermediate level following the current recommendations. This observation is predictable as based on previous publications a substantial number of subjects with iNPH over time develop AD. Thus, iNPH can be considered as a model of AD. We noted a surprisingly remarkable neuronal preservation assessing Neuronal Nuclei (NeuN) in parallel with a substantial depletion of matrix/neuropil. This finding is intriguing as it suggests that loss of matrix/neuropil might be one of the first lesion of ADNC but also a hallmark lesion of iNPH. The latter observation is in line with the enlarged ventricles, a cardinal feature of iNPH. Furthermore, a positive correlation was observed between the extent of A beta and NeuN but only in females indicating a neuronal preservation even when A beta pathology is present. The assessment of a surgical biopsy as described here is certainly informative and thus it is surprising that a neuropathologic assessment in the setting of iNPH, while inserting a shunt, is seldom performed. Here, we observed ADNC and surprisingly remarkable neuronal preservation in a substantial number of iNPH subjects. Thus, these subjects allow us to observe the natural course of the disease and give us an opportunity for intervention at the earliest stages of AD, prior to severe neuronal damage.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2019
Nyckelord
Alzheimer's disease Neuropathologic change, Idiopathic Normal pressure hydrocephalus, Neuronal loss, Matrix/neuropil, Immunohistochemistry
Nationell ämneskategori
Neurovetenskaper Neurologi
Identifikatorer
urn:nbn:se:uu:diva-390602 (URN)10.1186/s40478-019-0748-9 (DOI)000473753900001 ()31142354 (PubMedID)
Forskningsfinansiär
Hans-Gabriel och Alice Trolle-Wachtmeisters stiftelse för medicinsk forskning
Tillgänglig från: 2019-08-13 Skapad: 2019-08-13 Senast uppdaterad: 2021-02-03Bibliografiskt granskad
4. In vivo characterisation of biochemical variants of amyloid β in subjects with idiopathic Normal Pressure Hydrocephalus and Alzheimer’s Disease Neuropathological Change
Öppna denna publikation i ny flik eller fönster >>In vivo characterisation of biochemical variants of amyloid β in subjects with idiopathic Normal Pressure Hydrocephalus and Alzheimer’s Disease Neuropathological Change
(Engelska)Ingår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908Artikel i tidskrift (Refereegranskat) Accepted
Nyckelord
biochemical variants, amyloid β, idiopathic Normal Pressure Hydrocephalus, Alzheimer’s Disease Neuropathologic Change
Nationell ämneskategori
Annan medicinsk grundvetenskap
Forskningsämne
Patologi; Geriatrik
Identifikatorer
urn:nbn:se:uu:diva-433959 (URN)
Tillgänglig från: 2021-02-03 Skapad: 2021-02-03 Senast uppdaterad: 2021-02-03

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